The science of drug discovery has greatly benefited in recent years from dramatic advances made in scientific research and development. For example, on one end of the drug discovery spectrum, the concerted international effort to sequence the human genome has led to the discovery of large numbers of genes and gene products that are potential targets for pharmaceutical agents in the treatment of disease. On the other side of the equation, numerous approaches to combinatorial chemical synthesis have led to the generation of extremely large numbers of different chemical compounds that can be screened for effects on those targets.
Linking the two technologies are a number of advances in technology for screening the large libraries of compounds against large collections of targets. For example, large automated robotic systems have been developed to sample and mix reagents from libraries in multiwell plate formats, performing thousands of different screening reactions in a single day. These systems employ a brute force approach to screening potential pharmaceutical compounds by automating the fluid handling components of the assay process. While these systems are widely used, they provide only a first incremental increase in efficiency over the lone experimenter working at his or her bench. Further, given the ever-expanding numbers of screening assays that are required, it has not taken long for this incremental increase in efficiency to be surpassed by the screening demand.
Microfluidic technology is one of the most recent technologies to be applied in screening pharmaceutical libraries (see, e.g., U.S. Pat. No. 5,942,443). These microfluidic technologies provide benefits in terms of reagent consumption, speed, reproducibility and automatability. Specifically, when performed in the microscale format in fluid volumes on the order of nanoliters or less, reagents mix more quickly, and assays require much smaller quantities of expensive reagents. Further, the integrated nature of microfluidic systems allows for precise computer control of material flow, mixing, data acquisition and analysis allowing for ease of use and improved reproducibility.
Microfluidic systems have also been developed to interface with the traditional library storage format, namely the multiwell plate. In particular, pipettor chips have been developed that include an external sample accessing capillary, see, e.g., U.S. Pat. No. 5,779,868. While such systems provide the advantages of smaller reagent requirements in screening, conventional library storage systems still utilize large reagent volumes, effectively eliminating some of the advantages otherwise provided by microfluidic technology.
While all of the foregoing advances in screening technology have provided significant benefits to the pharmaceutical industry, it would generally be desirable to be able to take advantage of all of the advantages of microfluidic technology in terms of the reagent storage and accessibility. The present invention meets these and a variety of other needs.
The present invention is generally directed to improved methods, devices and systems for use in high-throughput and even ultra high-throughput assays. Generally, the methods, devices and systems take advantage of novel automation, miniaturization and integration techniques to achieve these goals.
For example, in a first aspect, the present invention provides a method of sampling compounds into a microfluidic channel. In these methods, a plurality of different compounds are provided reversibly immobilized on a first surface of a substrate. A capillary element is also provided having a capillary channel disposed therethrough, where the capillary element has at least one open end, and a volume of solubilizing fluid present at the open end of the capillary element. In accordance with these methods, the solubilizing fluid at the open end of the capillary element is moved into contact with a first compound on the surface of the substrate by sensing when the solubilizing fluid contacts the surface of the substrate. The solubilizing fluid dissolves at least a portion of the first compound, and at least a portion of the dissolved first compound is drawn into the capillary element.
In another aspect, the present invention provides methods of sampling compounds into a microfluidic channel, which, in addition to providing the compounds reversibly immobilized on a substrate, and a capillary, as above, also comprises a drop of solubilizing fluid suspended from the open end of the capillary. The drop of solubilizing fluid suspended from the open end of the capillary element is moved relative to the substrate to place the drop into contact with a first compound immobilized on the first surface of the substrate. At least a portion of the compound solubilized by the drop of solubilizing fluid is then drawn into the microfluidic channel within the capillary element. These steps may be repeated multiple times with respect to one or multiple compounds on the substrate surface.
The present invention also generally provides devices and systems for carrying out the methods described herein or methods similar thereto. For example, in one aspect, the present invention provides systems for analyzing a plurality of different sample materials. The systems typically comprise a microfluidic element comprising a capillary element having at least a first microfluidic channel disposed therethrough, the capillary element having at least one open end The system also typically includes a sample substrate comprising a plurality of different sample materials reversibly immobilized thereon, each different sample being immobilized in a different discrete region of the first surface. A translation system is provided attached to at least one of the substrate or the microfluidic element, for moving either the microfluidic element relative to the substrate surface or vice versa. The system provides for a sensing system for sensing when a volume of fluid at the open end of the capillary element contacts the first surface of the substrate.